The organelle known as the mitochondrion is the main energy source in cells of higher organisms. Mitochondria provide direct and indirect biochemical regulation of a wide array of cellular respiratory, oxidative and metabolic processes. These include electron transport chain (ETC) activity, which drives oxidative phosphorylation to produce metabolic energy in the form of adenosine triphosphate (ATP), and which also underlies a central mitochondrial role in intracellular calcium homeostasis.
Mitochondrial respiration occurs on the inner mitochondrial membrane and is achieved by the flow of electrons through the electron transport system, which contains four complexes (complex I, II, III, and IV) with a further complex (complex V) serving as a site for ATP synthesis (ATP synthase). Impairment or reduction of activity of any complex disrupts electron flow and may cause mitochondrial respiratory dysfunction (See, e.g., Schildgen et al., Exp Hematol 2011; 39:666-67510, 11; Arthur et al., Mol Neurodegener 2009; 4:37). Analysis of mitochondrial metabolic dysfunction may be monitored by oxygen electrode analysis (See, e.g., Chance and Williams, J Biol Chem 1955; 217:383-393). Analysis has permitted an intimate understanding of mitochondrial respiratory function. The association between mitochondrial respiratory malfunction (e.g., leading to cell death, reactive oxygen species production, increased oxidative DNA damage, increased autophagy, loss of mitochondrial membrane potential (e.g., via aberrant Complex I expression and/or activity) and associated decreased ATP production) and a multitude of diseases and conditions (e.g., diabetes, obesity, aging related neurodegeneration including Alzheimer's disease, stroke, insulin resistance, atherosclerosis, etc.) has been extensively documented (See, e.g., Miguel et al., Exp Gerontol 1980; 15:575-591; McLean et al., Pharmacol Rev 2004; 56:163-184; Kujoth et al., Science 2005; 309:481-484; Guarente, Cell 2008; 132:171-176; Lopez-Lluch et al., Exp Gerontol 2008; 43:813-819; Shigenaga et al., Proc Natl Acad Sci USA 1994; 91:10771-10778; Schaefer et al., Biochim Biophys Acta 2004; 1659:115-120).